Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome.

BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 × 10-8) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0×10-6). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10-10 in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.

Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome.

OBJECTIVE: IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase-isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. DESIGN: We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. RESULTS: CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). CONCLUSIONS: SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.

Increased Prevalence of Rare Sucrase-isomaltase Pathogenic Variants in Irritable Bowel Syndrome Patients.

Patients with irritable bowel syndrome (IBS) often associate their symptoms to certain foods. In congenital sucrase-isomaltase deficiency (CSID), recessive mutations in the SI gene (coding for the disaccharidase digesting sucrose and 60% of dietary starch)1 cause clinical features of IBS through colonic accumulation of undigested carbohydrates, triggering bowel symptoms.2 Hence, in a previous study,3 we hypothesized that CSID variants reducing SI enzymatic activity may contribute to development of IBS symptoms. We detected association with increased risk of IBS for 4 rare loss-of-function variants typically found in (homozygous) CSID patients, because carriers (heterozygous) of these rare variants were more common in patients than in controls.1,4 Through a 2-step computational and experimental strategy, the present study aimed to determine whether other (dys-)functional SI variants are associated with risk of IBS in addition to known CSID mutations. We first aimed to identify all SI rare pathogenic variants (SI-RPVs) on the basis of integrated Mendelian Clinically Applicable Pathogenicity (M-CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; next, we inspected genotype data currently available for 2207 IBS patients from a large ongoing project to compare SI-RPV case frequencies with ethnically matched population frequencies from the Exome Aggregation Consortium (ExAC).

Chronic constipation diagnosis and treatment evaluation: the "CHRO.CO.DI.T.E." study.

BACKGROUND: According to Rome criteria, chronic constipation (CC) includes functional constipation (FC) and irritable bowel syndrome with constipation (IBS-C). Some patients do not meet these criteria (No Rome Constipation, NRC). The aim of the study was is to evaluate the various clinical presentation and management of FC, IBS-C and NRC in Italy. METHODS: During a 2-month period, 52 Italian gastroenterologists recorded clinical data of FC, IBS-C and NRC patients, using Bristol scale, PAC-SYM and PAC-QoL questionnaires. In addition, gastroenterologists were also asked to record whether the patients were clinically assessed for CC for the first time or were in follow up. Diagnostic tests and prescribed therapies were also recorded. RESULTS: Eight hundred seventy-eight consecutive CC patients (706 F) were enrolled (FC 62.5%, IBS-C 31.3%, NRC 6.2%). PAC-SYM and PAC-QoL scores were higher in IBS-C than in FC and NRC. 49.5% were at their first gastroenterological evaluation for CC. In 48.5% CC duration was longer than 10 years. A specialist consultation was requested in 31.6%, more frequently in IBS-C than in NRC. Digital rectal examination was performed in only 56.4%. Diagnostic tests were prescribed to 80.0%. Faecal calprotectin, thyroid tests, celiac serology, breath tests were more frequently suggested in IBS-C and anorectal manometry in FC. More than 90% had at least one treatment suggested on chronic constipation, most frequently dietary changes, macrogol and fibers. Antispasmodics and psychotherapy were more frequently prescribed in IBS-C, prucalopride and pelvic floor rehabilitation in FC. CONCLUSIONS: Patients with IBS-C reported more severe symptoms and worse quality of life than FC and NRC. Digital rectal examination was often not performed but at least one diagnostic test was prescribed to most patients. Colonoscopy and blood tests were the "first line" diagnostic tools. Macrogol was the most prescribed laxative, and prucalopride and pelvic floor rehabilitation represented a "second line" approach. Diagnostic tests and prescribed therapies increased by increasing CC severity.

Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome.

BACKGROUND & AIMS: SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5. METHODS: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. RESULTS: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. CONCLUSIONS: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.

Italian guidelines for the management of irritable bowel syndrome: Joint Consensus from the Italian Societies of: Gastroenterology and Endoscopy (SIGE), Neurogastroenterology and Motility (SINGEM), Hospital Gastroenterologists and Endoscopists (AIGO), Digestive Endoscopy (SIED), General Medicine (SIMG), Gastroenterology, Hepatology and Pediatric Nutrition (SIGENP) and Pediatrics (SIP).

The irritable bowel syndrome (IBS) is a chronic disorder of gut-brain interaction. IBS is still associated with areas of uncertainties, especially regarding the optimal diagnostic work-up and the more appropriate management. Experts from 7 Italian Societies conducted a Delphi consensus with literature summary and voting process on 27 statements. Recommendations and quality of evidence were evaluated using the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. Consensus was defined as >80% agreement and reached for all statements. In terms of diagnosis, the consensus supports a positive diagnostic strategy with a symptom-based approach, including the psychological comorbidities assessment and the exclusion of alarm symptoms, together with the digital rectal examination, full blood count, C-reactive protein, serology for coeliac disease, and fecal calprotectin assessment. Colonoscopy should be recommended in patients with alarm features. Regarding treatment, the consensus strongly supports a dietary approach for patients with IBS, the use of soluble fiber, secretagogues, tricyclic antidepressants, psychologically directed therapies and, only in specific IBS subtypes, rifaximin. A conditional recommendation was achieved for probiotics, polyethylene glycol, antispasmodics, selective serotonin reuptake inhibitors and, only in specific IBS subtypes, 5-HT3 antagonists, 5-HT4 agonists, bile acid sequestrants.

Upper Gastrointestinal Endoscopy Quality in Italy: A Nationwide Study.

BACKGROUND AND AIMS: International guidelines advise improving esophagogastroduodenoscopy (EGD) quality in Western countries, where gastric cancer is still diagnosed in advanced stages. This nationwide study investigated some indicators for the quality of EGD performed in endoscopic centers in Italy. METHODS: Clinical, endoscopic, and procedural data of consecutive EGDs performed in one month in the participating centers were reviewed and collected in a specific database. Some quality indicators before and during endoscopic procedures were evaluated. RESULTS: A total of 3,219 EGDs performed by 172 endoscopists in 28 centers were reviewed. Data found that some relevant information (family history for GI cancer, smoking habit, use of proton pump inhibitors) were not collected before endoscopy in 58.5-80.7% of patients. Pre-endoscopic preparation for gastric cleaning was routinely performed in only 2 (7.1%) centers. Regarding the procedure, sedation was not performed in 17.6% of patients, and virtual chromoendoscopy was frequently (>75%) used in only one (3.6%) center. An adequate sampling of the gastric mucosa (i.e., antral and gastric body specimens) was heterogeneously performed, and it was routinely performed only by 23% of endoscopists, and in 14.3% centers. CONCLUSIONS: Our analysis showed that the quality of EGD performed in clinical practice in Italy deserves to be urgently improved in different aspects.

IBS clinical management in Italy: The AIGO survey.

BACKGROUND: Irritable bowel syndrome (IBS) is the most frequent functional gastrointestinal disorder, both in primary and secondary care. AIMS: (1) To describe diagnostic tools and treatments suggested to IBS patients by Italian gastroenterologists; (2) To evaluate patients' quality of life and psychological involvement and the relationship of these factors with symptom severity. METHODS: Twenty-six gastroenterologists recorded the demographic and clinical data of 677 IBS patients. Diagnostic and treatment measures taken in the previous year and those suggested by gastroenterologists were analysed. RESULTS: IBS with constipation was found in 43.4%, with diarrhoea in 21.6%, mixed-IBS in 35.0%. Routine blood tests, ultrasonography, colonoscopy, barium enema and CT were more frequently requested in the previous year than by the gastroenterologists (p < 0.001). Colonoscopy (11%), and ultrasonography (20.4%) were also suggested by the gastroenterologists in a non-negligible number of patients. Abdominal pain and distension, bowel dissatisfaction, anxiety and depression were more severe in females than in males. Quality of life decreased with increasing IBS-symptom severity. CONCLUSIONS: IBS diagnosis is still largely based on exclusion criteria even if gastroenterologists try to improve diagnostic appropriateness. However, therapy remains symptom-based also in the gastroenterological setting even if gastroenterologists use a wide variety of approaches, including innovative therapies such as linaclotide and psychotherapy.

Pancreaticoduodenectomy for dysplastic duodenal adenoma in a patient with familial adenomatous polyposis.

Colorectal polyposis is the main feature of familial adenomatous polyposis (FAP), but benign and malignant lesions have also been described in the stomach, duodenum, small bowel, biliary tract and pancreas. There are few reports on FAP patients with duodenal polyps that developed at a younger age and even fewer on cases with dysplastic degeneration. The progression to carcinoma usually presents quite late in the clinical history of FAP patients, typically at least 20 to 25 years after proctocolectomy. This report described the rare case of a patient presenting with duodenal adenomas with dysplastic changes and tumor infiltration as the first sign of FAP, who was treated by pancreaticoduodenectomy followed by proctocolectomy for subsequent dysplastic changes in colonic polyps.

Practice guidelines on the use of esophageal manometry - A GISMAD-SIGE-AIGO medical position statement.

Patients with esophageal symptoms potentially associated to esophageal motor disorders such as dysphagia, chest pain, heartburn and regurgitation, represent one of the most frequent reasons for referral to gastroenterological evaluation. The utility of esophageal manometry in clinical practice is: (1) to accurately define esophageal motor function, (2) to identify abnormal motor function, and (3) to establish a treatment plan based on motor abnormalities. With this in mind, in the last decade, investigations and technical advances, with the introduction of high-resolution esophageal manometry, have enhanced our understanding and management of esophageal motility disorders. The following recommendations were developed to assist physicians in the appropriate use of esophageal manometry in modern patient care. They were discussed and approved after a comprehensive review of the medical literature pertaining to manometric techniques and their recent application. This position statement created under the auspices of the Gruppo Italiano di Studio per la Motilità dell'Apparato Digerente (GISMAD), Società Italiana di Gastroenterologia ed Endoscopia Digestiva (SIGE) and Associazione Italiana Gastroenterologi ed Endoscopisti Digestivi Ospedalieri (AIGO) is intended to help clinicians in applying manometric studies in the most fruitful manner within the context of their patients with esophageal symptoms.

Short article: Relapsing Whipple's disease: a case report and literature review.

Whipple's disease is a rare infection caused by Tropheryma whipplei, a Gram-negative Bacillus usually found in macrophages of the lamina propria of the small intestine. The typical clinical manifestations of classic Whipple's disease are diarrhea, weight loss, malabsorption, abdominal pain, and arthralgia. The disease's laboratory diagnosis is currently based on duodenal biopsy. Treatment generally includes primary therapy for 2 weeks with intravenous antibiotics capable of reaching high levels in the cerebrospinal fluid, such as ceftriaxone, usually followed by treatment with oral cotrimoxazole for 1 year. Early diagnosis should enable appropriate treatment and improves the prognosis, and prolonged antibiotic treatment often leads to complete remission. Our case report focuses on a 72-year-old man who had been passing watery stools for 1-2 months, accompanied by low-grade fever. He reported profound asthenia, a weight loss of about 3 kg, and loss of appetite. Thirty years earlier (in 1984), he had been working as a horse keeper at a University Department of Agricultural and Veterinary Studies, where he had contracted Whipple's disease. Laboratory tests and microbiological studies led to a diagnosis of recurrent Whipple's disease. Esophagogastroduodenoscopy was performed under deep sedation. Biopsy samples obtained from the stomach and duodenum were stained with hematoxylin and eosin, Giemsa, and periodic acid-Schiff to identify any accumulation of typical periodic acid-Schiff-positive macrophages in the lamina propria. A specific quantitative real-time PCR assay using specific oligonucleotide probes for targeting repeated sequences of Tropheryma whipplei was also performed to detect its DNA in the duodenum samples.

The Impact of Heller Myotomy on Integrated Relaxation Pressure in Esophageal Achalasia.

BACKGROUND: A new high-resolution manometry (HRM) parameter, the integrated relaxation pressure (IRP), has been proposed for the assessment of esophageal-gastric junction (EGJ) relaxation. Our aim was to assess the effect of Heller myotomy on IRP in achalasia patients. METHODS: We prospectively collected data on achalasia patients who underwent HRM between 2009-2014. Barium swallow was used to assess esophageal diameter and shape. Manometric diagnoses were performed by using the Chicago Classification v3. All patients with a confirmed diagnosis of achalasia were treated surgically with Heller Myotomy RESULTS: One hundred thirty-nine consecutive achalasia patients (M:F = 72:67) represented the study population. All the patients had 100% simultaneous waves but 11 had an IRP < 15 mmHg. At median follow-up of 28 months, the median of IRP was significantly lower after surgery (27.4 [IQR 20.4-35] vs 7.1 [IQR 4.4-9.8]; p < 0.001), and so were the lower esophageal sphincter (LES) resting pressure (27 [IQR 18-33] vs 6 [IQR 3-11]; p < 0.001). At univariate analysis, IRP correlated with the gender, LES resting residual pressure, and dysphagia score. CONCLUSIONS: This is the first study to have examined the role of IRP in achalasia, and how it changes after surgical treatment. An increased preoperative IRP correlated directly with a more severe dysphagia. The IRP was restored to normal by Heller myotomy.

Beneficial effect of auto-aggregating Lactobacillus crispatus on experimentally induced colitis in mice.

We tested the therapeutic relevance of auto aggregation in lactobacilli by comparing the effect on DSS induced colitis of viable Lactobacillus crispatus M247, isolated from healthy humans, to L. crispatus MU5, an isogenic spontaneous mutants of M247, the latter lacking the auto aggregation phenotype which allows the adhesion to human mucus. Aggregating L. crispatus M247, but not the non-aggregating MU5, was retrievable from mice feces and adherent to the colonic mucosa. Daily administration of L. crispatus M247, but not heat killed L. crispatus M247 or aggregation deficient L. crispatus MU5, dose-dependently reduced the severity of DSS colitis. Indeed, L. crispatus MU5 administered in a 30% sucrose solution, known to restore the aggregation phenotype, had a protective effect comparable to mice receiving L. crispatus M247. These results indicate that a surface-mediated property such as aggregation may play a pivotal role in the protective effects obtained by dietary supplementation with L. crispatus M247 during colitis.

Clinical, endoscopic, histological and radiological characteristics of Italian patients with eosinophilic oesophagitis.

BACKGROUND: Limited data are available on eosinophilic oesophagitis in Italy. AIM: To evaluate typical features of eosinophilic oesophagitis patients in a tertiary centre. METHODS: 973 consecutive patients with dysphagia and/or bolus impaction were prospectively enrolled and underwent upper endoscopy for eosinophilic oesophagitis (≥15 eosinophils in at least one high-power field [hpf] and no response to acid suppressants). Demographic and multiple clinical factors were collected. RESULTS: 45 patients (80% males, mean age 35±16) with incident eosinophilic oesophagitis (mean eosinophil peak count 57.2±40.6/hpf) were enrolled. 32 patients complained of solids dysphagia (71%), and 29 of bolus impaction (64%). Endoscopy found rings in 20 (44%), furrows in 9 (20%), whitish exudates/plaques in 12 (27%), crêpe paper in 7 (13%) and normal findings in 14 patients (31%). Endoscopic and radiologic stenosis occurred in 20 (44%) and 23 (51%), respectively. Ten patients had proton pump inhibitor-oesophageal eosinophilia (22%). Topic fluticasone was effective in 28 of the remaining cases (62%), while 7 required additional treatments (16%). CONCLUSION: Eosinophilic oesophagitis prevalence was 12% in patients with dysphagia and/or bolus impaction, emphasizing the importance of this disease in Italy. Despite different environmental factors and dietary habits, Italian patients with eosinophilic oesophagitis present similar characteristics to those of other Western counties.

Diagnosis and treatment of faecal incontinence: Consensus statement of the Italian Society of Colorectal Surgery and the Italian Association of Hospital Gastroenterologists.

Faecal incontinence is a common and disturbing condition, which leads to impaired quality of life and huge social and economic costs. Although recent studies have identified novel diagnostic modalities and therapeutic options, the best diagnostic and therapeutic approach is not yet completely known and shared among experts in this field. The Italian Society of Colorectal Surgery and the Italian Association of Hospital Gastroenterologists selected a pool of experts to constitute a joint committee on the basis of their experience in treating pelvic floor disorders. The aim was to develop a position paper on the diagnostic and therapeutic aspects of faecal incontinence, to provide practical recommendations for a cost-effective diagnostic work-up and a tailored treatment strategy. The recommendations were defined and graded on the basis of levels of evidence in accordance with the criteria of the Oxford Centre for Evidence-Based Medicine, and were based on currently published scientific evidence. Each statement was drafted through constant communication and evaluation conducted both online and during face-to-face working meetings. A brief recommendation at the end of each paragraph allows clinicians to find concise responses to each diagnostic and therapeutic issue.

(13)C-octanoic acid breath test (OBT) with a new test meal (EXPIROGer): Toward standardization for testing gastric emptying of solids.

BACKGROUND: Standardization of the (13)C-octanoic acid breath test is still lacking. AIM: To evaluate the accuracy of the (13)C-octanoic acid breath test using a new standardized ready-to-eat, gluten-, glucose-, and lactose-free muffin. METHODS: Healthy subjects were recruited and sorted by sex and age. Patients with diabetic gastroparesis and untreated celiac disease with known gastric motility disorders were also tested with the new labelled muffin. Expired breath (13)CO(2) was analysed and t(1/2) was calculated. RESULTS: Overall, 131 healthy subjects were enrolled. The reference range of t(1/2) was 88+/-29min with the value of 146min as the upper limit of normal range. No significant difference in t(1/2) was found among subjects sorted by sex or age. The within-subject variability of t(1/2) was 17%. Mean (+/-standard deviation) t(1/2) values were 179+/-50min in patients with diabetic gastroparesis (n=8) and 151+/-20min in those with untreated celiac disease (n=11) (p

Role of M-CSF-dependent macrophages in colitis is driven by the nature of the inflammatory stimulus.

Although macrophages are considered a critical factor in determining the severity of acute inflammatory responses in the gut, recent evidence has indicated that macrophages may also play a counterinflammatory role. In this study, we examined the role of a macrophage subset in two models of colitis. Macrophage colony-stimulating factor (M-CSF)-deficient osteopetrotic mice (op/op) and M-CSF-expressing heterozygote (+/?) mice were studied following the induction of colitis by either dinitrobenzene sulfonic acid (DNBS) or dextran sulfate sodium (DSS). DNBS induced a severe colitis in M-CSF-deficient op/op mice compared with +/? mice. This was associated with increased mortality and more severe macroscopic and microscopic injury. Colonic tissue myeloperoxidase (MPO) activity as well as concentrations of TNF-alpha, IL-1beta, and IL-6 were higher and IL-10 lower in op/op mice with DNBS colitis. The severity of inflammation and mortality was attenuated in op/op mice that had received human recombinant M-CSF prior to the induction of colitis. In contrast, op/op mice appeared less vulnerable to colitis induced by DSS. Macroscopic damage, microscopic injury, MPO activity, and tissue concentrations of TNF-alpha, IL-1beta, and IL-6 were all lower in op/op mice compared with +/? mice with DSS colitis, and no changes were seen in IL-10. Macrophage inflammatory protein-1alpha concentrations were increased in op/op but not +/? mice following colitis induced by DNBS but not DSS. These results indicate that M-CSF-dependent macrophages may play either a pro- or counterinflammatory role in acute experimental colitis, depending on the stimulus used to induce colitis.

TGF-beta1 gene transfer to the mouse colon leads to intestinal fibrosis.

Crohn's disease (CD) is a chronic, relapsing inflammatory bowel disease, characterized by transmural inflammation. In CD, the recurrent inflammatory injury and tissue repair that occurs in the intestine can progress uncontrollably, leading to the proliferation of mesenchymal cells as well as fibrosis, characterized by excessive extracellular matrix deposition. These processes thicken the bowel wall, reducing flexibility, and often culminate in obstructive strictures. Because no effective measures are currently available to specifically treat or prevent intestinal stricturing, we sought to gain a better understanding of its pathogenesis by developing a mouse model of intestinal fibrosis. Because transforming growth factor (TGF)-beta1 can mediate both fibrosis and mesenchymal cell proliferation; we studied the effects of delivering adenoviral vectors encoding spontaneously active TGF-beta1 into the colons of mice. We first demonstrated that enema delivery of marker adenoviral vectors led to the transfection of the colonic epithelium and transient transgene expression. Histologically, control vectors caused an acute inflammatory response, involving the recruitment of neutrophils and mononuclear cells into the colonic lamina propria; however, infection caused little if any fibrosis. In contrast, the TGF-beta1 vector caused a more severe and prolonged inflammatory response as well as localized collagen deposition, leading to severe and progressive fibrosis. This was accompanied by the emergence of cells with a myofibroblast phenotype. Ultimately the fibrosis resulted in many of the TGF-beta1-transfected mice developing profound colonic obstruction. Through adenoviral gene transfer technology, we describe a novel mouse model of colitis and implicate TGF-beta1 in the pathogenesis of obstructive intestinal fibrosis.